Aside from the generally accepted potential to cause DNA damage, it is becoming increasingly recognized that ionizing radiation has the capability to target the cellular epigenome. Epigenetics unifies the chemical marks and molecules that collectively facilitate the proper reading of genetic material. Among the epigenetic mechanisms of regulation, methylation of DNA is known to be the key player in the postirradiation response by controlling the expression of genetic information and activity of transposable elements. Radiation-induced alterations to DNA methylation may lead to cellular epigenetic reprogramming that, in turn, can substantially compromise the genomic integrity and has been proposed as one of the mechanisms of radiation-induced carcinogenesis. DNA methylation is strongly dependent on the one-carbon metabolism. This metabolic pathway is central to the support of DNA methylation by means of providing the donor of methyl groups, as well as for the synthesis of amino acids. To better understand the mechanisms of radiation-induced health effects, we study how exposure to radiation affects DNA methylation and one-carbon metabolism. Also, a tight interaction that exists between DNA methylation and one-carbon metabolism allows us to simultaneously manipulate both cellular epigenetic and metabolic profiles to modulate the normal and cancerous tissue response to radiotherapy.